Potential new therapeutic target for inflammatory diseases found

International research led by Trinity College Dublin

Deborah Condon

March 15, 2023

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  • A group of international scientists, led by a team at Trinity College Dublin (TCD), has discovered a potential new therapeutic target for inflammatory diseases such as sepsis, lupus and arthritis.

    The scientists have found that a particular enzyme – fumarate hydratase – is repressed in macrophages. Macrophages are a type of white blood cell that are essential in the immune system. They are implicated in a number of diseases, such as sepsis and lupus.

    According to the lead author of the research, Prof Luke O’Neill of TCD, no-one has so far made a link between fumarate hydratase and inflammatory macrophages before.

    “We feel that this process might be targetable to treat debilitating diseases like lupus, which is a nasty autoimmune disease that damages several parts of the body including the skin, kidneys and joints,” Prof O’Neill explained.

    As part of the research, fumarate hydratase was shown to be repressed in a model of sepsis, an often-fatal systemic inflammatory condition that can occur during bacterial and viral infections. Similarly, in blood samples from patients with lupus, fumarate hydratase was dramatically decreased. 

    “We have made an important link between fumarate hydratase and immune proteins called cytokines that mediate inflammatory diseases. We found that when fumarate hydratase is repressed, RNA is released from mitochondria which can bind to key proteins ‘MDA5’ and ‘TLR7’ and trigger the release of cytokines, thereby worsening inflammation. This process could potentially be targeted therapeutically,” explained the research’s joint first author, Christian Peace.

    According to Prof O’Neill, restoring fumarate hydratase in these diseases or targeting MDA5 and TLR7 “presents an exciting prospect for badly needed new anti-inflammatory therapies”.

    The scientists noted that newly published work by a group led by Prof Christian Frezza of the University of Cologne and Dr Julien Prudent at the MRC Mitochondrial Biology Unit, have made similar findings in the context of kidney cancer. 

    “Because the system can go wrong in certain types of cancer, the scope of any potential therapeutic target could be widened beyond inflammation,” Prof O’Neill pointed out.

    The research involved a collaboration between eight universities including TCD and the MRC MBU at the University of Cambridge. Cedars Sinai Medical Centre in the US was also another key collaborator. The findings are published in the journal, Nature.

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